Metabotropic (i.e., G protein coupled) receptors are known to contribute to normal synaptic function and long-term modulation of neuronal function in the CNS. However, little is known about how ethanol alters the physiological responses initiated by metabotropic receptor activation. Preliminary data presented in this research proposal show that acute ethanol exposure of CNS neurons modulates changes in excitability evoked by metabotropic glutamate receptor (mGluR) agonists, and that the effects of ethanol are dependent on the mGluR agonist tested. Moreover, the data suggest that coactivation of multiple mGluR subtypes unmasks additional actions of ethanol on the cell. These results suggest that the actions of ethanol on the neuron are dependent on the relative level of physiological activation of the different mGluR subtypes. The experiments outlined in this research proposal will address the involvement of mGluRl and mGluR7 in the effects of ethanol on neuronal excitability. mGluRl and mGluR7 are representative of the two major subfamilies of mGluRs, those that activate phospholipase C (mGluR1) and those that regulate adenylyl cyclase activity (mGluR7). In addition, the ethanol sensitivity of the signaling pathways coupled to the mGluRs, including calcium signaling, will be assessed. Ethanol is expected to modulate transduction pathways linked to mGluRs because previous studies have shown ethanol sensitivity of several components of these intracellular signaling pathways, including G proteins, regulatory enzymes (e.g., protein kinase C and adenylyl cyclase), and intracellular calcium release. The purpose of this R03 application is to develop an independent research plan in the form of an RO1 application in a future funding period by obtaining preliminary data that can be used to generate hypotheses regarding the effects of ethanol on metabotropic receptor-evoked neuronal activity. Results from these studies should also lead to a better understanding of the cellular mechanisms that underlie the actions of ethanol in the CNS.